Association between NPPA promoter methylation and hypertension: results from Gusu cohort and replication in an independent sample

BACKGROUND: Atrial natriuretic peptide (ANP), one of the main members of the natriuretic peptides system, has been associated with hypertension and related complications, but the underlying molecular mechanisms are not very clear. Here, we aimed to examine whether DNA methylation, a molecular modification to the genome, of the natriuretic peptide A gene (NPPA), the coding gene of ANP, was associated with hypertension. METHODS: Peripheral blood DNA methylation of NPPA promoter was quantified by target bisulfite sequencing in 2498 community members (mean aged 53 years, 38% men) as a discovery sample and 1771 independent participants (mean aged 62 years, 54% men) as a replication sample. In both samples, we conducted a single CpG association analysis, followed by a gene-based association analysis, to examine the association between NPPA promoter methylation and hypertension, adjusting for age, sex, education level, cigarette smoking, alcohol consumption, obesity, fasting glucose, and lipids. Multiple testing was controlled by the false discovery rate approach. RESULTS: Of the 9 CpG loci assayed, hypermethylation at 5 CpGs (CpG1, CpG3, CpG6, CpG8, and CpG9) was significantly associated with a lower odds of prevalent hypertension in the discovery sample, and one CpG methylation (CpG1 located at Chr1:11908353) was successfully replicated in the replication sample (OR = 0.82, 95%CI 0.74–0.91, q = 0.002) after adjusting for covariates and multiple testing. The gene-based analysis found that DNA methylation of the 9 CpGs at NPPA promoter as a whole was significantly associated with blood pressure and prevalent hypertension in both samples (all P < 0.05). CONCLUSIONS: DNA methylation levels at NPPA promoter were decreased in Chinese adults with hypertension. Aberrant DNA methylation of the NPPA gene may participate in the mechanisms of hypertension.